{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T07:19:23Z","timestamp":1793085563294,"version":"4.5.0"},"reference-count":21,"publisher":"American Physiological Society","issue":"2","funder":[{"name":"NIH","award":["NHLBI RO1"],"award-info":[{"award-number":["NHLBI RO1"]}]},{"name":"NIH","award":["HL 95077"],"award-info":[{"award-number":["HL 95077"]}]},{"name":"NIH","award":["HL131017"],"award-info":[{"award-number":["HL131017"]}]},{"name":"NIH","award":["HL114120"],"award-info":[{"award-number":["HL114120"]}]},{"name":"UO1","award":["HL134168"],"award-info":[{"award-number":["HL134168"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2018,8,1]]},"abstract":"<jats:p>\n                    The microenvironment of native heart tissue may be better replicated when cardiomyocytes are cultured in three-dimensional clusters (i.e., spheroids) than in monolayers or as individual cells. Thus, we differentiated human cardiac lineage-induced pluripotent stem cells in cardiomyocytes (hiPSC-CMs) and allowed them to form spheroids and spheroid fusions that were characterized in vitro and evaluated in mice after experimentally induced myocardial infarction (MI). Synchronized contractions were observed within 24 h of spheroid formation, and optical mapping experiments confirmed the presence of both Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients and propagating action potentials. In spheroid fusions, the intraspheroid conduction velocity was 7.0\u2009\u00b1\u20093.8 cm\/s on days 1\u2013 2 after formation, whereas the conduction velocity between spheroids increased significantly ( P = 0.003) from 0.8\u2009\u00b1\u20091.1 cm\/s on days 1\u2013 2 to 3.3\u2009\u00b1\u20091.4 cm\/s on day 7. For the murine MI model, five-spheroid fusions (200,000 hiPSC-CMs\/spheroid) were embedded in a fibrin patch and the patch was transplanted over the site of infarction. Later (4 wk), echocardiographic measurements of left ventricular ejection fraction and fractional shortening were significantly greater in patch-treated animals than in animals that recovered without the patch, and the engraftment rate was 25.6% or 30% when evaluated histologically or via bioluminescence imaging, respectively. The exosomes released from the spheroid patch seemed to increase cardiac function. In conclusion, our results established the feasibility of using hiPSC-CM spheroids and spheroid fusions for cardiac tissue engineering, and, when fibrin patches containing hiPSC-CM spheroid fusions were evaluated in a murine MI model, the engraftment rate was much higher than the rates we have achieved via the direct intramyocardial injection.\n                  <\/jats:p>\n                  <jats:p>NEW &amp; NOTEWORTHY Spheroids fuse in culture to produce structures with uniformly distributed cells. Furthermore, human cardiac lineage-induced pluripotent stem cells in cardiomyocytes in adjacent fused spheroids became electromechanically coupled as the fusions matured in vitro, and when the spheroids were combined with a biological matrix and administered as a patch over the infarcted region of mouse hearts, the engraftment rate exceeded 25%, and the treatment was associated with significant improvements in cardiac function via a paracrine mechanism, where exosomes released from the spheroid patch.<\/jats:p>","DOI":"10.1152\/ajpheart.00688.2017","type":"journal-article","created":{"date-parts":[[2018,4,6]],"date-time":"2018-04-06T15:51:41Z","timestamp":1523029901000},"page":"H327-H339","source":"Crossref","is-referenced-by-count":79,"title":["Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice"],"prefix":"10.1152","volume":"315","author":[{"given":"Saidulu","family":"Mattapally","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir G.","family":"Fast","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea","family":"Worley","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramaswamy","family":"Kannappan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton V.","family":"Borovjagin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, School of Engineering, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-0942-4"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu167"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2017.01.029"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.030785"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.310277"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/term.46"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00751.2013"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.150"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-56106-6_5"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306985"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.08.024"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.100"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.09.013"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2010.03.001"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.05.020"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.269894"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2014.11.009"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.114.001317"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00178.2017"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311504"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nm1394"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00688.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T23:11:46Z","timestamp":1567984306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00688.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,1]]},"references-count":21,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2018,8,1]]}},"alternative-id":["10.1152\/ajpheart.00688.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00688.2017","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,1]]}}}